Long-Term Effects Following Acute Exposure to Sarin Nerve Agent

The National
Toxicology Program, on behalf of the National Institutes of Health (NIH)
Countermeasures Against Chemical Threats (CounterACT) program, recently
conducted a systematic review to evaluate the evidence for long-term
neurological effects in humans and animals following acute exposure to sarin.

Sarin is a highly
toxic organophosphorus nerve agent that was developed for chemical warfare
during World War II and continues to be used as a weapon. Long-term
neurological effects of acute exposure to sarin are not well characterized. Previous
reviews of potential health effects of sarin have generally not assessed
individual study quality or considered multiple evidence streams (human,
animal, and mechanistic data). In addition, the interpretation of effects of
sarin in some previous reviews was compounded by concurrent exposure to
multiple chemicals, such as assessments of health effects in military personnel
during the Gulf War or other conflicts.

The literature search
and screening process identified 32 datasets within the 34 human studies and 47
datasets within the 51 animal studies (from 6,837 potentially relevant
references) that met the objective and the inclusion criteria.

Neurological Response Health Effect Findings Author’s note: These are select summary points curated from the report. Please read the full NTP draft for complete context of the findings.

Cholinesterase Levels

There is a high level
of evidence from the human studies that sarin decreased cholinesterase levels
in the initial time period and a moderate level of evidence for decreased
cholinesterase from experimental animal studies. The evidence for potential
effects on cholinesterase in the extended period is inadequate with no
experimental data and only a single study in humans.

Visual and Ocular Effects

Case reports or case
series have reported that subjects exposed to sarin occupationally or via
terrorist attacks complained of vision problems for weeks to years after
exposure. There is a consistent pattern of findings that pupil constriction
from acute sarin exposure gradually normalizes in the following week to several
months. There is a moderate level of evidence from human studies that sarin has
negative effects on vision in the intermediate time period including decreases
in visual evoked potentials.

Learning, Memory, and Intelligence

Experimental studies
in rats found consistent sarin-related effects on learning and memory that were
apparent for days, weeks, and months after sarin exposure. The evidence from
human studies for effects on learning and memory during the initial period is
inadequate. In the extended period, there is a moderate level of evidence that
sarin exposure is associated with impaired learning and memory based on
epidemiological studies and a low level of evidence from experimental animal
studies.

Morphology and Histopathology in Nervous System
Tissues

Although there were no
experimental animal studies available to evaluate morphological and
histological changes at the extended time period after exposure, one
cross-sectional study and one case report, which evaluated adults from the
Tokyo subway attack, provide evidence that acute exposure to high levels of
sarin is associated with morphological and histological changes in human
nervous system tissues in the years following sarin exposure.

Key Data Gaps

Rapid Research Response

Because wartime and
terrorist use of chemical weapons are rare and unpredictable events, there
could be value to developing a rapid research response capability so that
emergency response would include the latest treatment knowledge for the
victims. The response could also collect vital human clinical data soon after
chemical exposures.

Well designed,
pre-planned, epidemiological studies would add valuable data to the body of
evidence that would be likely to impact conclusions or the confidence in the
conclusions reached in this systematic review, given the lack of human data on
many endpoints and time periods.

More rigorous human
data would add greater confidence to conclusions reached in this evaluation
across all outcomes described above except in the body of evidence for
suppression of cholinesterase activity in the initial time period, which
already is rated as high confidence and a high level of evidence.

Data on other
persistent symptoms and neurological effects would also be valuable, as a range
of effects have been reported, but the evidence was inadequate to evaluate
these health outcomes due to serious limitations in the bodies of evidence
(e.g., heterogeneity in the endpoints examined, too few human or animal
studies, small sample sizes, serious risk-of-bias concerns).

Human Cohort Studies

Prospective
longitudinal cohort studies would be the most informative to better assess
neurological effects associated with sarin exposure. Studies that assess visual
and ocular effects 1 year or more after exposure in humans would address a data
gap in reaching conclusions. However, studies that evaluate measurable results
beyond pupil size and self-reported symptoms would add value to the assessment of
potential visual and ocular effects resulting from acute sarin exposure. Human
cohort studies would be invaluable in characterizing the relationship between
ChE activity and neurological effects over time, as well as the potential
relationship between acute sarin exposure and the development of PTSD as it
relates to other neurological effects.

Animal Model Dose-Response Effects Over Time

Because of the ability
to conduct controlled-exposure studies, experimental animal studies are
particularly important for addressing research gaps identified by this
systematic review, especially for identifying specific effects that could be
targeted for medical mitigation. Animal studies indicate differences in
inhibition and recovery of ChE activity in different areas of the brain;
however, the data are insufficient to identify if there are particularly
vulnerable areas of the brain. Future research could focus on these effects to
help identify potentially vulnerable areas that could be targeted. Studies in
appropriate animal models are also needed for rigorous, well-controlled
experimental assessments of the dose-response relationship between sarin
exposure and long-term neurological effects.

Sarin Effects on Special Populations

Another gap in both
the human and animal data are the effects of sarin on the developing and aging
brain. It currently cannot be assessed if children, the very young, or the very
old are more susceptible populations.